ABSTRACT Worldwide, there are 1.8 million children living with HIV-1 and ~150,000 new pediatric infections per year, approximately half of which occur due to HIV-1 transmission during breastfeeding. While antiretroviral therapy (ART) greatly reduces mortality and morbidity of HIV-1 infection, it is not a cure due to virus persistence in latent reservoirs. Strategies to reduce the persistent reservoir and promote virologic control in absence of ART (i.e., HIV-1 remission) would greatly benefit HIV-1-infected infants and children that now must remain on daily ART from the time of diagnosis through their entire life span. The Objective of this proposal is to test interventions that decrease residual immune activation and/or enhance antiviral immune responses in SIV-infected ART-treated infant rhesus macaques (RMs). Our Scientific Premise is that our novel model of postnatal oral SIV infection and suppressive ART in infant RMs will allow us to generate key data on the impact of immune interventions on residual immune activation, antiviral immune responses, virus reservoirs, and viral rebound following ART discontinuation. The interventions we will test, IL-21 and Ad26/MVA therapeutic vaccination with TLR7 stimulation (TV+TLR7), recently showed promising results in adult RMs and are predicted to favorably impact the immune dysfunction induced by HIV-1 infection in infants. The Central Hypothesis is that by targeting this immune dysfunction to reduce residual immune activation and/or boost virus-specific immune responses, we will decrease viral reservoirs and promote virologic control. We will test this hypothesis is in the following Specific Aims: 1) To determine the immunological impact of IL-21 or TV+TLR7 in SIV-infected ART-suppressed infant RMs; 2) To assess whether and to what extent IL-21 or TV+TLR7 reduces viral reservoirs in SIV-infected ART-suppressed infant RMs; and 3) To determine whether and to what extent IL-21 or TV+TLR7 results in delayed virus rebound or reduced viremia set point after ART interruption in SIV-infected infant RMs. A key feature of this proposal is that, by using our novel, highly relevant animal model of SIV infection and ART treatment, we are able to perform in-depth analyses of virus reservoirs and treatment interruption that would be impossible to conduct in pediatric participants. We expect the findings from this Project to critically inform HIV-1 cure efforts in the pediatric population.